DESCRIPTION (Adapted from the applicant?s abstract) This project proposes to continue the investigations of Dr. Creager and his team on the mechanism of abnormalities in vasomotor regulation in diabetics documented during the tenure of the Program Project in Vascular Medicine Biology to which this application is the successor. In the course of the work funded by the Vascular Medicine and Biology Program Project, Dr. Creager was able to show abnormalities in endothelium-dependent vasodilatation in the forearm circulation of patients with Type I and in both endothelium-dependent and independent vasodilatation in Type I diabetes. He was able to show that these abnormalities were independent of other variables associated with diabetes know to alter vasomotor function such as atherosclerosis and hypertension. Moreover, Dr. Creager showed that hyperglycemia per se, but not a non-glycemic osmotic challenge, could impair endothelial-dependent vasodilatation in the forearm. In the continuation of this line of research proposed here Dr. Creager will test specific mechanisms of the impaired vasomotor response as documented in the previous period. Extensive in vitro work suggests that diabetes augment protein kinase C activity in endothelial cells. Therefore, Dr. Creager will test whether certain isoforms of protein kinase C (i.e. PKCbeta) contribute to the abnormal vasodilator responses in this patient population. This work will make use of selective pharmacologic inhibitors. In addition to studying adults with Type I and Type II diabetes, Dr. Creager will extend his observations to offspring of patients with diabetes mellitus who have insulin resistance, but not overt diabetes, in collaboration with investigators at the Joslin Diabetes Center, nearby the Brigham and Women?s Hospital in the Longwood Medical/Academic Area. In other studies proposed in this project, Dr. Creager will test the hypothesis that activators of PPARs will ameliorate endothelium-dependent vasodilatation in diabetics. Specifically, this team will test the hypothesis that short term treatment with a thiazolidineidone PPAR-gamma activator will ameliorate the impaired flow-mediated vasodilatation in diabetic patients. Alteration in glycemia will be controlled for by euglycemic clamping. These studies will obviously provide direct clinical correlation with the laboratory studies on the roles of PPARs in control of vascular cell functions in Project 3. Hyperglycemia likely constitutes an oxidant stress for the endothelium, inspiring another major hypothesis to be tested in this project. Glutathione peroxidase (GPx) is a major cellular defense against oxidant stress. Dr. Creager?s team will use a GPx mimic to test whether augmenting this pathway will ameliorate the impaired vasodilator function in diabetic subjects. These experiments link explicitly with those proposed in the project 2, regarding the effect of elevated glucose levels and other stimuli on GPx activity in cultured endothelial cells in vitro. Dr. Creager and the investigators of Project 5 (Drs. Ganz, Selwyn, and Lanzberg) have successfully cross-fertilized over the last half dozen years under the aegis of the existing Vascular Medicine and Biology Program Project. Notably, findings made in the periphery have been extended in the coronary circulation where appropriate by Drs. Ganz and Selwyn. Shared fellows and publications indicate the close collaboration between Dr. Creager?s laboratory, which focuses on peripheral vascular function, and the Cardiac Catheterization Laboratory directed by Drs. Ganz and Selwyn, which focuses on the coronary and pulmonary circulations (see below and the biosketches for examples of joint publications).